Quinazoline derivatives, compositions thereof, and use as pharmaceuticals

ABSTRACT

Disclosed herein are protein kinase inhibitors, more particularly novel quinazoline derivatives and pharmaceutical compositions thereof, and method of use thereof.

FIELD OF THE INVENTION

This invention relates to novel quinazoline compounds and thepharmaceutically acceptable salts thereof. The compounds of the presentinvention may inhibit the epidermal growth factor receptor kinasesthereby inhibiting the abnormal growth of certain cell types. Thecompounds of this invention are useful for the treatment ofhyper-proliferative diseases such as cancer, in mammals and especiallyin humans. This invention also relates to the pharmaceuticalcompositions containing them and the use in the treatment of cancer.

BACKGROUND OF THE INVENTION

Protein tyrosine kinases are a class of enzymes that catalyze thetransfer of a phosphate group from ATP to a hydroxyl group on a tyrosineresidue located on a protein substrate. Since protein kinases playcritical roles in various cellular activities, deregulation of proteinkinase activity can lead to altered cellular properties, such asuncontrolled cell growth associated with cancer.

The epidermal growth factor receptor is a member of the ErbB family ofreceptors, a subfamily of four closely related receptor tyrosinekinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her4(ErbB-4). Mutations affecting EGFR expression or activity could resultin cancer.

Dysregulation of the epidermal growth factor receptor signaltransduction pathway has been implicated in tumorigenesis and cancerprogression thus making it a clinically relevant target for novelanticancer treatments. Several inhibitors of the epidermal growth factorreceptor signaling pathway have demonstrated clinical efficacy in cancertreatment. Small molecules such as gefitinib, erlotinib and lapatinib,as well as anti-EGFR antibodies cetuximab, panitumumab and trastuzumab,have been approved for the treatment of EGFR-overexpressing lungcancers.

Because of the emerging disease-related roles of epidermal growth factorreceptors, there is a continuing need for compounds which may be usefulfor treating and preventing a disease which responds to inhibition ofepidermal growth factor receptor(s) and have at least one advantageousproperty selected from potency, stability, selectivity, toxicity,pharmacodynamics properties and pharmacokinetics properties as analternative. In this regard, a novel class of epidermal growth factorreceptor inhibitors is provided herein.

DISCLOSURE OF THE INVENTION

Disclosed herein are certain novel quinazoline derivatives, compositionsthereof, and their use as pharmaceuticals.

In one aspect, disclosed herein is at least one compound of formula (I):

and/or at least one pharmaceutically acceptable salt thereof, wherein:

R¹ and R² are independently selected from hydrogen and C₁₋₆ alkyl,wherein alkyl is substituted with at least one substituent independentlyselected from the group consisting of hydroxyl, and C₁₋₆alkoxy;

R³ is selected from C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy,tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy,tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy,tetrahydropyran-4-ylmethoxy, (1,4-dioxan-2-yl)methoxy, and(3-oxa-bicyclo[3.1.0]hexan-6-yl)methoxy, wherein alkoxy and cycloalkoxyare independently unsubstituted or substituted with at least onesubstituent, such as one, two, three, or four substituents,independently selected from the group consisting of halogen, hydroxyl,C₁₋₆ alkyl, C₃₋₆ cycloalkyl and C₁₋₆ alkoxy;

Ar is selected from aryl, wherein aryl is substituted with at least onesubstituent, such as one, two, three, or four substituents,independently selected from the group consisting of halogen, hydroxyland cyano.

The invention further relates to a pharmaceutical composition for thetreatment of a hyperproliferative disorder in a mammal which comprises atherapeutically-effective amount of the compound of formula (I) and apharmaceutically acceptable carrier.

The invention further relates to a method of treating ahyperproliferative disorder in a mammal which comprises administering tosaid mammal a therapeutically-effective amount of the compound offormula (I).

In a preferred embodiment, the method of treating hyperproliferativedisorders includes those wherein said hyperproliferative disorder iscancer.

In another preferred embodiment, the method of treatinghyperproliferative disorders includes those wherein saidhyperproliferative disorder is noncancerous.

The invention further relates to a process for preparing a compound ofthe formula (I) or a pharmaceutically acceptable salt or prodrugthereof.

BRIEF DESCRIPTION OF THE FIGURES

The accompanying drawings, which are incorporated herein and form a partof the specification, illustrate non-limiting embodiments of the presentinvention, and together with the description, serve to explain theprinciples of the invention.

FIG. 1 shows a reaction scheme for the preparation of the compound offormula (I).

FIG. 2 shows the tumor inhibition of test compounds.

DETAILED DESCRIPTION OF THE INVENTION

As used herein the following definitions are applicable.

The term “alkyl” refers to both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms. Unless otherwise specified, “alkyl” refers to C₁₋₆alkyl. Forexample, C₁₋₆, as in “C₁₋₆ alkyl” is defined to include groups having 1,2, 3, 4, 5, or 6 carbons in a linear or branched arrangement. Forexample, “C₁₋₆alkyl” includes but is not limited to methyl, ethyl,n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl and hexyl.

The term “cycloalkyl” means a saturated aliphatic cyclic hydrocarbongroup having the specified number of carbon atoms. Unless otherwisespecified, “cycloalkyl” refers to C₃₋₆cycloalkyl. For example,“cycloalkyl” includes but is not limited to cyclopropyl,methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, andcyclohexyl.

The term “alkoxy” refers to either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove. “Cycloalkoxy” refers to a cyclic alkyl group of indicated numberof carbon atoms attached through an oxygen bridge.

The term “aryl” encompasses:

5- and 6-membered carbocyclic aromatic rings, for example, benzene;

bicyclic ring systems wherein at least one ring is carbocyclic andaromatic, for example, naphthalene, indane, and1,2,3,4-tetrahydroquinoline; and

tricyclic ring systems wherein at least one ring is carbocyclic andaromatic, for example, fluorene. In cases where the aryl substituent isbicyclic or tricyclic and at least one ring is non-aromatic, it isunderstood that attachment is via the aromatic ring.

For example, aryl includes 5- and 6-membered carbocyclic aromatic ringsfused to a 5- to 7-membered heterocyclic ring containing one or moreheteroatoms selected from N, O, and S, provided that the point ofattachment is at the carbocyclic aromatic ring. Bivalent radicals formedfrom substituted benzene derivatives and having the free valences atring atoms are named as substituted phenylene radicals. Bivalentradicals derived from univalent polycyclic hydrocarbon radicals whosenames end in “-yl” by removal of one hydrogen atom from the carbon atomwith the free valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a naphthyl group with two pointsof attachment is termed naphthylidene. Aryl, however, does not encompassor overlap in any way with heteroaryl, separately defined below. Hence,if one or more carbocyclic aromatic rings are fused with a heterocyclicaromatic ring, the resulting ring system is heteroaryl, not aryl, asdefined herein.

The term “halogen” (or “halo”) refers to fluorine, chlorine, bromine andiodine.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases may be selected, for example, from aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,manganic, manganous, potassium, sodium, and zinc salts. Further, forexample, the pharmaceutically acceptable salts derived from inorganicbases may be selected from ammonium, calcium, magnesium, potassium, andsodium salts. Salts in the solid form may exist in one or more crystalstructures, and may also be in the form of hydrates. Salts derived frompharmaceutically acceptable organic non-toxic bases may be selected, forexample, from salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N′-dibenzylethylene-diamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine, andtripropylamine, tromethamine.

When the compound disclosed herein is basic, salts may be prepared usingat least one pharmaceutically acceptable non-toxic acid, selected frominorganic and organic acids. Such acid may be selected, for example,from acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,and p-toluenesulfonic acids. In some embodiments, such acid may beselected, for example, from citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, fumaric, and tartaric acids.

The term “protecting group” or “Pg” refers to a substituent that can becommonly employed to block or protect a certain functionality whilereacting other functional groups on the compound. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include but are not limited to acetyl,trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protectinggroup” refers to a substituent of a hydroxy group that blocks orprotects the hydroxy functionality. Suitable protecting groups includebut are not limited to acetyl and silyl. A “carboxy-protecting group”refers to a substituent of the carboxy group that blocks or protects thecarboxy functionality. Common carboxy-protecting groups include—CH₂CH₂SO₂Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991.

The terms “administration of” and or “administering” at least onecompound and/or at least one pharmaceutically acceptable salt should beunderstood to mean providing at least one compound and/or at least onepharmaceutically acceptable salt thereof to the individual in recognizedneed of treatment.

The term “effective amount” means the amount of the at least onecompound and/or at least one pharmaceutically acceptable salt that willelicit the biological or medical response of a tissue, system, animal orhuman that is being sought by the researcher, veterinarian, medicaldoctor or other clinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to a pharmaceutical composition is intended to encompass aproduct comprising the active ingredient (s), and the inert ingredient(s) that make up the carrier, as well as any product which results,directly or indirectly, from combination, complexation or aggregation ofany two or more of the ingredients, or from dissociation of one or moreof the ingredients, or from other types of reactions or interactions ofone or more of the ingredients.

By “pharmaceutically acceptable” it is meant compatible with the otheringredients of the formulation and not unacceptably deleterious to therecipient thereof

In one embodiment, disclosed herein is at least one compound of formula(I):

and/or at least one pharmaceutically acceptable salt thereof, wherein:

R¹ and R² are independently selected from hydrogen and C₁₋₆ alkyl,wherein alkyl is substituted with at least one substituent independentlyselected from the group consisting of hydroxyl, and C₁₋₆ alkoxy;

R³ is selected from C₁₋₆ alkoxy, C₃₋₆ cycloalkoxy,tetrahydrofuran-3-yloxy, tetrahydrofuran-2-ylmethoxy,tetrahydrofuran-3-ylmethoxy, tetrahydropyran-4-yloxy,tetrahydropyran-4-ylmethoxy, (1,4-dioxan-2-yl)methoxy, and(3-oxa-bicyclo[3.1.0]hexan-6-yl)methoxy, wherein alkoxy and cycloalkoxyare independently unsubstituted or substituted with at least onesubstituent, such as one, two, three, or four substituents,independently selected from the group consisting of halogen, hydroxyl,C₁₋₆ alkyl, C₃₋₆ cycloalkyl and C₁₋₆ alkoxy;

Ar is selected from aryl, wherein aryl is substituted with at least onesubstituent, such as one, two, three, or four substituents,independently selected from the group consisting of halogen, hydroxyland cyano.

In some embodiments, R² is hydrogen.

In some embodiments, R¹ is C₁₋₆ alkyl, wherein alkyl is substituted withat least one substituent independently selected from the groupconsisting of hydroxyl and C₁₋₆ alkoxy. In further some embodiments, R¹is selected from hydroxymethyl, methoxymethyl and ethoxymethyl. Infurther some embodiments, R¹ is selected from hydroxymethyl andmethoxymethyl.

In some embodiments, R³ is selected from methoxy, ethoxy, methoxyethoxy,cyclopropylmethoxy, tetrahydrofuran-3-yloxy,tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy,tetrahydropyran-4-yloxy,tetrahydropyran-4-ylmethoxy,(1,4-dioxan-2-yl)methoxy, and(3-oxa-bicyclo[3.1.0]hexan-6-yl)methoxy.

In some embodiments, Ar is aryl, wherein aryl is substituted with atleast one substituent, such as one, two, three, or four substituents,independently selected from the group consisting of fluorine, chlorine,bromine and iodine.

In some embodiments, Ar is 3-chloro-4-fluorophenyl.

Also provided is at least one compound, selected from:

-   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(hydroxymethyl)    azetidin-1-yl)but-2-enamide;-   (R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide.-   (R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;-   (R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-((S)-tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-((S)-tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)    quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)    quinazolin-6-yl)-4-((R)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)    quinazolin-6-yl)-4-((S)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(7-(((S)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)    quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(7-(((S)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)    quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(7-((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(7-((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-((R)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide;-   (E)-N-(7-((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-((S)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide;    and/or pharmaceutically acceptable salts thereof.

Some of the compounds of Formula (I) have asymmetric carbon atoms. Suchdiasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known per se., for example, by chromatography and/or fractionalcrystallization. Enantiomers can be separated by converting theenantiomeric mixtures into a diastereomric mixture by reaction with anappropriate optically active compound (e.g., alcohol), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. All such isomers,including diastereomers mixtures and pure enantiomers are considered aspart of the invention.

The active compounds of this invention are potent inhibitors of the ErbBfamily of oncogenic and protooncogenic protein tyrosine kinases such asepidermal growth factor receptor (EGFR), ErbB2, HER3, or HER4 and thusare all adapted to therapeutic use as antiproliferative agents (e.g.,anticancer) in mammals, particularly humans. In particular, thecompounds of this invention are therapeutants or prophylactics for thetreatment of a variety of human tumors (renal, liver, kidney, bladder,breast, gastric, ovarian, colorectal, prostate, pancreatic, lung,vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, varioushead and neck tumors), and other hyperplastic conditions such as benignhyperplasia of the skin (e.g., psoriasis) or prostate (e.g., BPH). Itis, in addition, expected that a quinazoline of the present inventionmay possess activity against a range of leukemias and lymphoidmalignancies.

The active compounds may also be expected to be useful in the treatmentof additional disorders in which aberrant expression ligand/receptorinteractions, activation or signalling events related to various proteintyrosine kinases, whose activity is inhibited by the agents of FormulaI, are involved.

Such disorders may include those of neuronal, glial, astrocytal,hypothalamic, and other glandular, macrophagal, epithelial, stromal, andblastocoelic nature in which aberrant function, expression, activationor signalling of the ErbB tyrosine kinases may be involved. In addition,compounds of Formula I may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases which are inhibited by compounds ofFormula (I).

In accordance with the foregoing, the present disclosure also provides:

(1) a compound disclosed herein for use as a pharmaceutical;

(2) a compound disclosed herein for use as an ErbB family of receptorkinase inhibitor, for example, for use in any of the particularindications set forth above;

(3) a pharmaceutical composition, e.g. for use in any of the indicationsherein set forth above, comprising at least one compound disclosedherein as active ingredient together with one or more pharmaceuticallyacceptable diluents or carriers;

(4) a method for treatment of any particular indication set forth abovein a subject in need thereof which comprises administering an effectiveamount of at least one compound disclosed herein or at least onepharmaceutical composition comprising thereof;

(5) the use of a compound disclosed herein for making a medicament fortreatment or prevention of a disease or condition in which ErbB familyof receptor kinase play a role or is implicated;

(6) the method as defined above under (4) comprising co-administration,e.g. concomitantly or in sequence, of a therapeutically effective amountof a compound disclosed herein and one or more additional drugsubstances, said additional drug substance being useful in any of theparticular indications set forth above;

(7) a composition comprising a therapeutically effective amount of atleast one compound disclosed herein and at least one additional drugsubstance, wherein said additional drug substance is useful in any ofthe particular indications set forth above;

(8) use of a compound disclosed herein for making a medicament fortreatment or prevention of a disease which responds to inhibition of theErbB family of receptor kinase;

(9) the use according to (8), wherein the disease to be treated isselected from head and neck cancer, lung cancer (e.g., NSCLC), breastcancer, colon cancer, ovarian cancer, bladder cancer, gastric cancer,kidney cancer, skin cancer, pancreatic cancer, leukemias, lymphomas,esophageal cancer, uterine cancer or prostate cancer.

(10) the use according to (8) or (9), wherein the compound is apharmaceutically acceptable salt of any one of the examples disclosedherein;

(11) a method for the treatment of a disease which responds toinhibition of the ErbB family of receptor kinase, such as a diseaseselected from head and neck cancer, lung cancer (e.g., NSCLC), breastcancer, colon cancer, ovarian cancer, bladder cancer, gastric cancer,kidney cancer, skin cancer, pancreatic cancer, leukemias, lymphomas,esophageal cancer, uterine cancer or prostate cancer, comprisingadministering an effective amount of at least one compound disclosedherein and/or a pharmaceutically acceptable salt thereof. In someexamples, the compounds of the disclosure may be used alone or incombination with a chemotherapeutic agent to treat a cell proliferativedisorder, including but not limited to, lymphoma, osteosarcoma,melanoma, or a tumor of breast, renal, prostate, colorectal, thyroid,ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tumor.

Administration and Pharmaceutical Compositions

In general, compounds of the disclosure will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors known tothose of ordinary skill in the art. For example, for the treatment ofneoplastic diseases and immune system disorders, the required dosagewill also vary depending on the mode of administration, the particularcondition to be treated and the effect desired.

In general, satisfactory results are indicated to be obtainedsystemically at daily dosages of from about 0.001 to about 100 mg/kg perbody weight, or particularly, from about 0.03 to 2.5 mg/kg per bodyweight. An indicated daily dosage in the larger mammal, e.g. humans, maybe in the range from about 0.5 mg to about 2000 mg, or moreparticularly, from about 0.5 mg to about 100 mg, convenientlyadministered, for example, in divided doses up to four times a day or inretard form. Suitable unit dosage forms for oral administration comprisefrom ca. 1 to 50 mg active ingredient.

Compounds of the disclosure may be administered as pharmaceuticalcompositions by any conventional route; for example, enterally, e.g.,orally, e.g., in the form of tablets or capsules; parenterally, e.g., inthe form of injectable solutions or suspensions; or topically, e.g., inthe form of lotions, gels, ointments or creams, or in a nasal orsuppository form.

Pharmaceutical compositions comprising a compound of the presentdisclosure in free form or in a pharmaceutically acceptable salt form inassociation with at least one pharmaceutically acceptable carrier ordiluent may be manufactured in a conventional manner by mixing,granulating, coating, dissolving or lyophilizing processes. For example,pharmaceutical compositions comprising a compound of the disclosure inassociation with at least one pharmaceutical acceptable carrier ordiluent may be manufactured in conventional manner by mixing with apharmaceutically acceptable carrier or diluent. Unit dosage forms fororal administration contain, for example, from about 0.1 mg to about 500mg of active substance.

In one embodiment, the pharmaceutical compositions are solutions of theactive ingredient, including suspensions or dispersions, such asisotonic aqueous solutions. In the case of lyophilized compositionscomprising the active ingredient alone or together with a carrier suchas mannitol, dispersions or suspensions can be made up before use. Thepharmaceutical compositions may be sterilized and/or contain adjuvants,such as preserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure and/or buffers.Suitable preservatives include but are not limited to antioxidants suchas ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.The solutions or suspensions may further comprise viscosity-increasingagents, including but not limited to, sodium carboxymethylcellulose,carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatins, orsolubilizers, e.g. Tween 80 (polyoxyethylene(20)sorbitan mono-oleate).

Suspensions in oil may comprise as the oil component the vegetable,synthetic, or semi-synthetic oils customary for injection purposes.Examples include liquid fatty acid esters that contain as the acidcomponent a long-chained fatty acid having from 8 to 22 carbon atoms, orin some embodiments, from 12 to 22 carbon atoms. Suitable liquid fattyacid esters include but are not limited to lauric acid, tridecylic acid,myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearicacid, arachidic acid, behenic acid or corresponding unsaturated acids,for example oleic acid, elaidic acid, erucic acid, brassidic acid andlinoleic acid, and if desired, may contain antioxidants, for examplevitamin E, 3-carotene or 3,5-di-tert-butyl-hydroxytoluene. The alcoholcomponent of these fatty acid esters may have six carbon atoms and maybe monovalent or polyvalent, for example a mono-, di- or trivalent,alcohol. Suitable alcohol components include but are not limited tomethanol, ethanol, propanol, butanol or pentanol or isomers thereof;glycol and glycerol.

Other suitable fatty acid esters include but are not limitedethyl-oleate, isopropyl myristate, isopropyl palmitate, LABRAFIL® M2375, (polyoxyethylene glycerol), LABRAFIL® M 1944 CS (unsaturatedpolyglycolized glycerides prepared by alcoholysis of apricot kernel oiland comprising glycerides and polyethylene glycol ester), LABRASOL™(saturated polyglycolized glycerides prepared by alcoholysis of TCM andcomprising glycerides and polyethylene glycol ester; all available fromGaKefosse, France), and/or MIGLYOL® 812 (triglyceride of saturated fattyacids of chain length C8 to C12 from Hils AG, Germany), and vegetableoils such as cottonseed oil, almond oil, olive oil, castor oil, sesameoil, soybean oil, or groundnut oil.

Pharmaceutical compositions for oral administration may be obtained, forexample, by combining the active ingredient with one or more solidcarriers, and if desired, granulating a resulting mixture, andprocessing the mixture or granules by the inclusion of additionalexcipients, to form tablets or tablet cores.

Suitable carriers include but are not limited to fillers, such assugars, for example lactose, saccharose, mannitol or sorbitol, cellulosepreparations, and/or calcium phosphates, for example tricalciumphosphate or calcium hydrogen phosphate, and also binders, such asstarches, for example corn, wheat, rice or potato starch,methylcellulose, hydroxypropyl methylcellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if desired,disintegrators, such as the above-mentioned starches, carboxymethylstarch, crosslinked polyvinylpyrrolidone, alginic acid or a saltthereof, such as sodium alginate. Additional excipients include flowconditioners and lubricants, for example silicic acid, talc, stearicacid or salts thereof, such as magnesium or calcium stearate, and/orpolyethylene glycol, or derivatives thereof.

Tablet cores may be provided with suitable, optionally enteric, coatingsthrough the use of, inter alia, concentrated sugar solutions which maycomprise gum arable, talc, polyvinylpyrrolidone, polyethylene glycoland/or titanium dioxide, or coating solutions in suitable organicsolvents or solvent mixtures, or, for the preparation of entericcoatings, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Dyes or pigments may be added to the tablets or tablet coatings, forexample for identification purposes or to indicate different doses ofactive ingredient.

Pharmaceutical compositions for oral administration may also includehard capsules comprising gelatin or soft-sealed capsules comprisinggelatin and a plasticizer, such as glycerol or sorbitol. The hardcapsules may contain the active ingredient in the form of granules, forexample in admixture with fillers, such as corn starch, binders, and/orglidants, such as talc or magnesium stearate, and optionallystabilizers. In soft capsules, the active ingredient may be dissolved orsuspended in suitable liquid excipients, such as fatty oils, paraffinoil or liquid polyethylene glycols or fatty acid esters of ethylene orpropylene glycol, to which stabilizers and detergents, for example ofthe polyoxyethylene sorbitan fatty acid ester type, may also be added.

Pharmaceutical compositions suitable for rectal administration are, forexample, suppositories comprising a combination of the active ingredientand a suppository base. Suitable suppository bases are, for example,natural or synthetic triglycerides, paraffin hydrocarbons, polyethyleneglycols or higher alkanols.

Pharmaceutical compositions suitable for parenteral administration maycomprise aqueous solutions of an active ingredient in water-solubleform, for example of a water-soluble salt, or aqueous injectionsuspensions that contain viscosity-increasing substances, for examplesodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired,stabilizers. The active ingredient, optionally together with excipients,can also be in the form of a lyophilizate and can be made into asolution before parenteral administration by the addition of suitablesolvents. Solutions such as are used, for example, for parenteraladministration can also be employed as infusion solutions. Themanufacture of injectable preparations is usually carried out understerile conditions, as is the filling, for example, into ampoules orvials, and the sealing of the containers.

The compounds of the disclosure may be administered as the sole activeingredient, or together with other drugs useful against neoplasticdiseases or useful in immunomodulating regimens. For example, thecompounds of the disclosure may be used in accordance with thedisclosure in combination with pharmaceutical compositions effective invarious diseases as described above, e.g. with cyclophosphamide,5-fluorouracil, fludarabine, gemcitabine, cisplatinum, carboplatin,vincristine, vinblastine, etoposide, irinotecan, paclitaxel, docetaxel,rituxan, doxorubicine, gefitinib, or imatinib; or also withcyclosporins, rapamycins, ascomycins or their immunosuppressive analogs,e.g. cyclosporin A, cyclosporin G, FK-506, sirolimus or everolimus,corticosteroids, e.g. prednisone, cyclophosphamide, azathioprene,methotrexate, gold salts, sulfasalazine, antimalarials, brequinar,leflunomide, mizoribine, mycophenolic acid, mycophenolate, mofetil,15-deoxyspergualine, immuno-suppressive monoclonal antibodies, e.g.monoclonal antibodies to leukocyte receptors, e.g. MHC, CD2, CD3, CD4,CD7, CD25, CD28, I CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154,ICOS, LFA-1, VLA-4 or their ligands, or other immunomodulatorycompounds, e.g. CTLA41g.

The disclosure also provides for a pharmaceutical combinations, e.g. akit, comprising a) a first agent which is a compound of the disclosureas disclosed herein, in free form or in pharmaceutically acceptable saltform, and b) at least one co-agent. The kit can comprise instructionsfor its administration.

EXAMPLES

Various methods may be developed for synthesizing the at least onecompound of formula (I) and/or at least one pharmaceutically acceptablesalt thereof. Representative methods for synthesizing the at least onecompound of formula (I) and/or at least one pharmaceutically acceptablesalt thereof are provided in the Examples. It is noted, however, thatthe at least one compound of formula (I) and/or at least onepharmaceutically acceptable salt thereof may also be synthesized byother synthetic routes that others may devise.

It will be readily recognized that certain compounds of formula (I) haveatoms with linkages to other atoms that confer a particularstereochemistry to the compound (e.g., chiral centers). It is recognizedthat synthesis of the at least one compound of formula (I) and/or atleast one pharmaceutically acceptable salt thereof may result in thecreation of mixtures of different stereoisomers (enantiomers,diastereomers). Unless a particular stereochemistry is specified,recitation of a compound is intended to encompass all of the differentpossible stereoisomers.

The at least one compound of formula (I) can also be prepared as apharmaceutically acceptable acid addition salt by, for example, reactingthe free base form of the at least one compound with a pharmaceuticallyacceptable inorganic or organic acid. Alternatively, a pharmaceuticallyacceptable base addition salt of the at least one compound of formula(I) can be prepared by, for example, reacting the free acid form of theat least one compound with a pharmaceutically acceptable inorganic ororganic base. Inorganic and organic acids and bases suitable for thepreparation of the pharmaceutically acceptable salts of compounds offormula (I) are set forth in the definitions section of thisApplication. Alternatively, the salt forms of the compounds of formula(I) can be prepared using salts of the starting materials orintermediates.

The free acid or free base forms of the compounds of formula (I) can beprepared from the corresponding base addition salt or acid addition saltform. For example, a compound of formula (I) in an acid addition saltform can be converted to the corresponding free base thereof by treatingwith a suitable base (e.g., ammonium hydroxide solution, sodiumhydroxide, and the like). A compound of formula (I) in a base additionsalt form can be converted to the corresponding free acid thereof by,for example, treating with a suitable acid (e.g., hydrochloric acid,etc).

Protected derivatives of the compounds of formula (I) can be made bymethods known to those of ordinary skill in the art. A detaileddescription of the techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

The at least one compound of formula (I) and/or at least onepharmaceutically acceptable salt thereof may be conveniently prepared,or as solvates (e.g. hydrates). Hydrates of the at least one compound offormula I and/or at least one pharmaceutically acceptable salt thereofmay be conveniently prepared by recrystallization from anaqueous/organic solvent mixture, using organic solvents such as dioxin,tetrahydrofuran and/or methanol.

The compounds of formula (I) can also be prepared as their individualstereoisomers by reacting a racemic mixture of the compounds with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers, and recovering the opticallypure enantiomer. While resolution of enantiomers can be carried outusing covalent diasteromeric derivatives of compounds, dissociablecomplexes are preferred (e.g., crystalline diastereoisomeric salts).Diastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and can be readilyseparated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, for example, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. For example, the following abbreviations may be used inthe examples and throughout the specification: g (grams); mg(milligrams); L (liters); mL (milliliters); μL (microliters); psi(pounds per square inch); M (molar); mM (millimolar); i.v.(intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol(millimoles); RT (room temperature); min (minutes); h (hours); mp(melting point); TLC (thin layer chromatography); Rt (retention time);RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA(triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroaceticanhydride); THF (tetrahydrofuran); DMSO (dimethyl sulfoxide); EtOAc(ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE(dichloroethane); DMF (N,N-dimethylformamide); DMPU(N,N′-dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF(isobutyl chloroformate); HOAc (acetic acid); HOSu(N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et₂O (diethylether); EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride); BOC (tert-butyloxycarbonyl); FMOC(9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ(benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TMSE(2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS(triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP(4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); tBu(tert-butyl); HPLC (high pressure liquid chomatography); BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF(tetra-n-butylammonium fluoride); m-CPBA (meta-chloroperbenzoic acid).

References to ether or Et₂O are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionswere conducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Varian Mercury Plus 400. Chemicalshifts are expressed in parts per million (ppm). Coupling constants arein units of hertz (Hz). Splitting patterns describe apparentmultiplicities and are designated as s (singlet), d (doublet), t(triplet), q (quartet), m (multiplet), and br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Shimadzu LC/MS single quadrapole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60F-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, ninhydrin, orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

Synthetic Schemes

The at least one compound of formula (I) and/or at least onepharmaceutically acceptable salt thereof may be synthesized according toa variety of reaction schemes. Some illustrative schemes are providedbelow and in the examples. Other reaction schemes could be readilydevised by those skilled in the art in view of the present disclosure.

In the reactions disclosed below, it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for example,see T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

Synthetic methods for preparing the compounds in the present disclosureare illustrated in the following Schemes and Examples. Startingmaterials are commercially available or may be made according toprocedures known in the art or as illustrated herein.

Preparation of Compound of Formula (I)

Compound of formula (I) could be assembled by combination of4-bromo-enamide (II) with properly substituted amine (III) vianucleophilic substitution reaction in a polar solvent such as DMF in thepresence of base such as K₂CO₃.

Synthesis of Intermediate IIa

Intermediate IIa may be prepared as illustrated in the following FIG. 1.4-Chloro-7-fluoro-6-nitroquinazoline (iii) can be prepared by methodssimilar to those described in J. Med. Chem. 1996, 39, 918-928. Nitrationof fluoroquinazoline (i) provides 7-fluoro-6-nitro-3H-quinazolin-4-one(ii), which can be treated with thionyl chloride to give4-chloro-quinazoline (iii). Combination of 4-chloro-quinazoline (iii)with properly substituted aniline in a solvent such as isopropanol leadsto 4-anilino-quinazoline (iv). Treatment of 7-fluoro-quinazoline (iv)with sodium methoxide provides 7-methoxy-quinazoline (v). Hydrogenationof the 6-nitro compound (v) in the presence of a catalyst such as RaneyNickel provides the 6-amino analog (vi). The 6-amino-quinazoline (vi)may be reacted with a haloEGFRenoyl chloride, such as4-bromo-but-2-enoyl chloride (vii), to provide 4-bromo-eneamide IIa.HaloEGFRenoyl chloride are readily accessible through known procedures,such as treatment of alkenoic acid with halogenating agent such as NBSyielding the corresponding haloEGFRenoic acid, which may in turn betreated with oxalyl chloride to provide the desired haloEGFRenoylchloride.

Intermediates shown in the following Scheme 1 can be synthesized byusing the same procedure as described for intermediate IIa by replacingmethanol with the appropriate alcohols which are either commerciallyavailable or readily accessible through known procedures.

Finally, treatment of Intermediate II with a secondary amine III, whichare commercially available or readily accessible through knownprocedures, provides compound I.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshall not be construed as limiting the invention in any way.

Preparation of Intermediates Intermediate A

7-Fluoroquinazolin-4-ol (A-1)

A mixture of 2-amino-4-fluorobenzoic acid (3.00 g, 19.3 mmol) informamide (30 mL) was heated at 150° C. for 6 hours. The mixture waspoured into ice-water (1/1) (250 mL). The solid was collected byfiltration, washed with water and dried to give the title compound (A-1)as white solid. MS-ESI (m/z): 165 [M+H]+.

7-Fluoro-6-nitroquinazolin-4-ol (A-2)

A solution of 7-fluoroquinazolin-4-ol (A-1) in concentrated H₂SO₄ (100mL) and fuming HNO₃ (100 mL) was heated at 100° C. for 1 h. Aftercooling, the solution was poured into ice-water (1.5 L) to give amixture of 6- and 8-nitroquinazolin-4-ol. Recrystallization of themixture from AcOH gave title compound (A-2) as yellow solid. MS-ESI(m/z): 210 [M+H].

4-Chloro-7-fluoro-6-nitroquinazoline(A-3)

A suspension of 7-fluoro-6-nitroquinazolin-4-ol (A-2) (10.45 g, 50.00mmol) in SOCl₂ (200 mL) containing catalytic amount of DMF was heatedunder reflux for 3 h to give a clear solution. The SOCl₂ was removedunder vacuum to give the crude title compound (A-3) which was directlyused in next step.

N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine(A-4)

To a solution of crude 4-chloro-7-fluoro-6-nitroquinazoline (A-3) in DCM(100 mL) was added a solution of 3-chloro-4-fluorobenzenamine (7.97 g,54.8 mmol) in i-PrOH (250 mL). The resulting mixture was stirred at r.t.for 15 min. Petroleum ether (800 mL) was added to ensure completeprecipitation. Solid was collected by filtration to give the titlecompound (A-4). MS-ESI (m/z): 337 [M+H]⁺.

N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine(A-5)

To a solution of NaOMe (28.0 g, 518 mmol) in of dry MeOH (1.5 L) underN₂ on a cooling bath was addedN-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (A-4)(72.76 g, 219 mmol). The cooling bath was removed and the mixture washeated at reflux for 1 h. The reaction was cooled to r.t. and quenchedwith water until the product precipitated. The solid was collected byfiltration and washed with water and Et₂O, and dried to give the titlecompound (A-5) as yellow solid. MS-ESI (m/z): 349 [M+H]⁺.

N⁴-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine(A-6)

To a solution ofN-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine (A-5)(31.81 g, 91.22 mmol) in THF was added Raney Ni (4 g). The mixture wasstirred at r.t. for 12 h under H₂ balloon. The catalyst was removed byfiltration. The filtrates were concentrated to about 50 mL. Then HCl/EAwas added slowly followed by MTBE. The precipitate was collected byfiltration, dried to give the title compound (A-6) as hydrochloride.MS-ESI (m/z): 319 [M+H]⁺.

(E)-4-bromo-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)but-2-enamide(Intermediate A)

To a solution of crotonic acid (10.0 g, 116 mmol) in CCl₄ (100 mL) wasaddedN-bromosuccinimide (21.4 g, 120 mmol) followed by benzoyl peroxide(0.20 g, 0.83 mmol). The mixture was refluxed for 4.5 h, and then cooledto r.t. The mixture was stored in fridge overnight. The crystals werefiltered off and the filtrate was evaporated. The residue wasrecrystallized from hexane to give (E)-4-bromobut-2-enoic acid as whitesolid.

To a solution of (E)-4-bromobut-2-enoic acid (0.825 g, 5.00 mmol) in DCM(10 mL) was added (COCl)₂ (1.27 g, 10.0 mmol) followed by DMF (about 50μL). The mixture was stirred at r.t. for 4.5 h. Solvents wereevaporated, the residue was re-dissolved in 5 mL of THF (solution A).

To a stirred mixture of A-6 (800 mg, 2.25 mmol) in a mixture of THF (10mL), EtOAc (10 mL) and saturated NaHCO₃ (40 mL) was added solution Adropwise at 0° C. Then the mixture was stirred at r.t. for 30 min. Theorganic layer was separated and the aqueous layer was extracted withEtOAc (40 mL). The combined organic layer was washed with brine, driedover Na₂SO₄ and evaporated. The residue was purified by columnchromatography (hexanes: EtOAc=2:1) to give the title compound as yellowsolid. MS-ESI (m/z): 465 [M+1]⁺.

Intermediate B(E)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)but-2-enamide(Intermediate B)

Intermediate B was prepared by using the same procedure as described forIntermediate A by replacing methanol with ethanol.

Intermediate C(E)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(cyclopropylmethoxy)quinazolin-6-yl)but-2-enamide (Intermediate C)

Intermediate C was prepared by using the same procedure as described forIntermediate A by replacing methanol with cyclopropylmethanol.

Intermediate D(E)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-methoxyethoxy)quinazolin-6-yl)but-2-enamide (Intermediate D)

Intermediate D was prepared by using the same procedure as described forIntermediate A by replacing methanol with 2-methoxyethanol.

Intermediate E(S,E)-4-bromo-N-(4-((3-chloro-4-fluorophenyl)amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)but-2-enamide(Intermediate E)

Intermediate E was prepared by using the same procedure as described forIntermediate A by replacing methanol with (S)-tetrahydrofuran-3-ol.

Intermediate F

(R)-1-(2-bromoethoxy)-3-chloropropan-2-ol (F-1)

To a solution of 2-bromoethanol (12.86 mL, 191.8 mmol) and BF₃.Et₂O(0.45 mL, 3.2 mmol) was added (R)-2-(chloromethyl)oxirane dropwise at45° C. The reaction mixture was heated at 45° C. for 2 h. After cooledto r.t., diethyl ether (100 mL) was added to the mixture. The solutionwas washed with water, dried over Na₂SO₄ and concentrated to give thetitle compound (F-1) as light brown liquid.

(R)-2-((2-bromoethoxy)methyl)oxirane (F-2)

(R)-1-(2-bromoethoxy)-3-chloropropan-2-ol (F-1) (11 g, 64 mmol) wasadded dropwise to a stirred solution of NaOH (6.36 g, 159 mmol) in water(7.6 mL) at 0° C. The mixture was stirred at 25° C. for 2 h. Thendiethyl ether and water were added. The organic layer was separated andwashed with water, dried over sodium sulfate and concentrated to givethe title compound (F-2) as light brown liquid.

(S)-(1,4-dioxan-2-yl)methanol (F-3)

(R)-2-((2-bromoethoxy)methyl)oxirane (F-2) (5.5 g, 41 mmol) was added toan aqueous solution of NaOH (4.09 g, 102 mmol, 40 mL) at r.t. Themixture was heated to 90° C. and stirred for 2 h. The resulting mixturewas saturated by adding solid K₂CO₃, and extracted with DCM (6×40 mL).The combined organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by column chromatography with EtOAc/petroleum ether(2:1-3:1) to give the title compound (F-3) as clear liquid.

(R,E)-N-(7-((1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-bromobut-2-enamide (Intermediate F)

Intermediate F was prepared by using the same procedure as IntermediateA by replacing methanol with F-3. MS-ESI (m/z): 551 (M+1)⁺.

Intermediate G(S,E)-N-(7-((1,4-dioxan-2-yl)methoxy)-4-((3-chloro-4-fluorophenyl)amino)quinazolin-6-yl)-4-bromobut-2-enamide (Intermediate G)

Intermediate G was prepared by using the same procedure as described forIntermediate F by replacing (R)-2-(chloromethyl)oxirane with(S)-2-(chloromethyl)oxirane.

Intermediate H

(1R,5S,6R)-ethyl 3-oxabicyclo[3.1.0]hexane-6-carboxylate (H-1)

To a solution of 2,5-dihydro-furan (7.00 g, 100 mmol) in DCM (100 mL)was added Rh₂(OAc)₄ (0.22 g, 0.50 mmol) in one portion To the abovesolution was added a solution of ethyl 2-diazoacetate (12.0 mL, 0.1 mol)in DCM (50 mL) dropwise over 2.5 h. The reaction mixture was stirred atr.t. for 15 h. Then silica gel (20 g) was added to the mixture, afterstirring vigorously for 5 min, the mixture was concentrated in vacuo andpurified by flash column chromatography, eluted with hexanes/EtOAc(10:0-10:1) to give the title compound H-1 (6.0 g).

(1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-ylmethanol (H-2)

To a solution of H-1 (3.10 g, 20.0 mmol) in THF (40 mL) at 0° C. wasadded a solution of LiAlH₄ in THF (15.0 mL, 2.0 M, 30.0 mmol) dropwise.The mixture was warmed to r.t. and stirred for 1 h. After re-cooling to0° C., NaSO₄.10H₂O (10 g) was added to the above mixture in 3 portionswith precaution, the mixture was vigorously stirred for 1 h, and driedover MgSO₄. Filtration and concentration in vacuo gave the titlecompound H-2 (2.1 g).

(E)-N-(7-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-bromobut-2-enamide (Intermediate H)

Intermediate H was prepared by using the same procedure as IntermediateA by replacing methanol with H-2.

Example 1(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide (1)

Azetidin-2-ylmethanol hydrochloride (1a)

The title compound was prepared by using the same procedure as describedin J. Med. Chem. 2008, 51, 948-956.

(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide (1)

A mixture of azetidin-3-ylmethanol hydrochloride (1a) (50 mg, 0.4 mmol),Na₂CO₃ (100 mg, 0.8 mmol) in 3 mL DMF was stirred at r.t. for 0.5 h, andintermediate A (80 mg, 0.2 mmol) was added. The mixture was stirred atr.t for 1 h. The reaction was quenched with water (30 mL), and extractedwith EtOAc (2×50 mL). The extracts were washed with water, brine, driedand concentrated. The residue was purified by column chromatographyeluting with DCM/MeOH (15:1) to give the title compound (1) 40 mg as ayellow solid. MS-ESI (m/z): 472 [M+1]⁺.

Example 2(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(2)

(R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (2a)

The title compound was prepared starting from commercial availabledibenzyl ester of D-aspartic acid using the same procedure as describedin Tetrahedron: Asymmetry 1998, 9, 2791-2794.

(R)-tert-butyl 2-(methoxymethyl)azetidine-1-carboxylate (2b)

A solution of (R)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate(2a) (510 mg, 2.73 mmol) in 10 mL DMF was added NaH (60% 218 mg, 5.46mmol) in portions at 0° C., and stirred for 0.5 hour. MeI (581 mg, 4.09mmol) was added to the mixture and warmed to r.t. in 2 h. The reactionwas quenched with ice-water (50 mL) and extracted with EtOAc (35 mL×3).The extracts were washed with brine (35 mL×2), dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography, elutedwith hexanes/EtOAc (6:1) to give 2b (260 mg) as colourless oil. MS-ESI(m/z): 202 [M+1]⁺.

(R)-2-(methoxymethyl)azetidine trifluoroacetic acid salt (2c)

To a solution of tert-butyl 2-(methoxymethyl)azetidine-1-carboxylate(260 mg, 1.29 mmol) in DCM (5 mL) was added trifluoroacetic acid (1.5mL). The mixture was stirred at r.t. for 1 h. The reaction mixture wasconcentrated to give crude product of 2c and used in next step withoutpurification. MS-ESI (m/z): 102 [M+1]⁺.

(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(2)

The title compound was prepared by using the same procedure as describedfor Example 1 by replacing 1a with 2c. MS-ESI (m/z): 486 [M+1]⁺.

Example 3(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(3)

The title compound was prepared by using the same procedure as describedfor Example 2 by replacing dibenzyl ester of D-aspartic acid withdibenzyl ester of L-aspartic acid. MS-ESI (m/z): 486 [M+1]⁺.

Example 4(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(4)

The title compound was prepared by using the same procedure as describedfor Example 2 by replacing intermediate A with intermediate B. MS-ESI(m/z): 500 [M+H]⁺.

Example 5(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(5)

The title compound was prepared by using the same procedure as describedfor Example 3 by replacing intermediate A with intermediate B. MS-ESI(m/z): 500 [M+H]⁺.

Example 6(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(6)

The title compound was prepared by using the same procedure as describedfor Example 2 by replacing intermediate A with intermediate D. MS-ESI(m/z): 530 [M+H]⁺.

Example 7(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(7)

The title compound was prepared by using the same procedure as describedfor Example 3 by replacing intermediate A with intermediate D. MS-ESI(m/z): 530 [M+H]⁺.

Example 8(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide(8)

The title compound was prepared by using the same procedure as describedfor Example 1 by replacing intermediate A with intermediate C. MS-ESI(m/z): 512 [M+H]⁺.

Example 9(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(9)

The title compound was prepared by using the same procedure as describedfor Example 2 by replacing intermediate A with intermediate C. MS-ESI(m/z): 526 [M+H]⁺.

Example 10(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(10)

The title compound was prepared by using the same procedure as describedfor Example 3 by replacing intermediate A with intermediate C. MS-ESI(m/z): 526 [M+H]⁺.

Example 11(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-((S)-tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide(11)

The title compound was prepared by using the same procedure as describedfor Example 1 by replacing intermediate A with intermediate E. MS-ESI(m/z): 528 [M+H]⁺.

Example 12(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-((S)-tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(12)

benzyl 1-benzylazetidine-2-carboxylate (12a)

A mixture of benzyl 2,4-dibromobutanoate (8.50 g, 25.2 mmol),benzylamine (4.05 g, 37.8 mmol) and K₂CO₃ (8.70 g, 63.1 mmol) inAcetonitrile (70 mL) was heated to 85° C. overnight. The mixture wascooled to room temperature and filtered. The cake was washed with EtOAc(30 mL). The combined filtrate was concentrated under reduced pressure.The residue was purified by column chromatography on silica gel elutingwith PE/EtOAc (20:1˜10:1) to give the title compound 12a (4.0 g) asyellow oil. MS-ESI (m/z): 282.0 [M+1]⁺.

1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (12b)

A mixture of 12a (3.70 g, 13.2 mmol), Di-tert butyl dicarbonate (5.70 g,26.3 mmol), and Pd(OH)₂ (0.90 g, 6.43 mmol) in MeOH (100 mL) was stirredunder H₂ atmosphere at 50° C. for 7 hours. The reaction mixture wascooled to room temperature and filtered. The filtrate was treated with 2N NaOH (40 mL) and stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure. The residue wasextracted with EtOAc (50 mL). The liquid phase was acified with 1 N HCl,adjusted pH=2 and extracted with DCM:i-PrOH=4:1 (150 mL×3). The combinedorganic layers was washed with water (100 mL), dried over Na₂SO₄ andconcentrated under reduced pressure to give the title compound 12b (2.50g) as colorless oil. MS-ESI (m/z): 146.0 [M+1−56]⁺.

tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (12c)

To a solution of 12b (1.45 g, 7.21 mmol) in anhydrous THF (12 mL) wasadded dropwise Borane-methyl sulfide complex (10M, 3 mL) at 0° C. Thereaction mixture was warmed to room temperature for 3 hours. Then it wasquenched with MeOH (10 mL), diluted with DCM (100 mL), washed with water(40 mL×3), dried over Na₂SO₄ and concentrated under reduced pressure togive the title compound 12c (1.25 g) as colorless oil. MS-ESI (m/z):132.0 [M+1−56]⁺.

2-(methoxymethyl)azetidine trifluoroacetic acid salt (12d)

The title compound was prepared by using the same procedure as describedfor 2c by replacing 2b with 12c. MS-ESI (m/z): 102 [M+H]⁺.

(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-((S)-tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide(12)

The title compound was prepared by using the same procedure as describedfor Example 1 prepared from intermediate E and 12d. MS-ESI (m/z): 542[M+H]⁺.

Example 13(E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide (13)

The title compound was prepared by using the same procedure as describedfor Example 1 by replacing intermediate A with intermediate F. MS-ESI(m/z): 558 [M+H]⁺.

Example 14(E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-((R)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide(14)

The title compound was prepared by using the same procedure as describedfor Example 2 by replacing intermediate A with intermediate F. MS-ESI(m/z): 572 [M+H]⁺.

Example 15(E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-((S)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide(15)

The title compound was prepared by using the same procedure as describedfor Example 3 by replacing intermediate A with intermediate F. MS-ESI(m/z): 572 [M+H]⁺.

Example 16(E)-N-(7-(((S)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide (16)

The title compound was prepared by using the same procedure as describedfor Example 1 by replacing intermediate A with intermediate G. MS-ESI(m/z): 558 [M+H]⁺.

Example 17(E)-N-(7-(((S)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide (17)

The title compound was prepared by using the same procedure as describedfor Example 12 by replacing intermediate E with intermediate G. MS-ESI(m/z): 572 [M+H]⁺.

Example 18(E)-N-(7-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide(18)

The title compound was prepared by using the same procedure as describedfor Example 1 by replacing intermediate A with intermediate H. MS-ESI(m/z): 554 [M+H]⁺.

Example 19(E)-N-(7-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-((R)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide(19)

The title compound was prepared by using the same procedure as describedfor Example 2 by replacing intermediate A with intermediate H. MS-ESI(m/z): 568 [M+H]⁺.

Example 20(E)-N-(7-((1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-((S)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide(20)

The title compound was prepared by using the same procedure as describedfor Example 3 by replacing intermediate A with intermediate H. MS-ESI(m/z): 568 [M+H]⁺.

Cell Proliferation Asssay Materials and Preparation of Reagents

MTS testing kit was purchased from Promega. The RPMI-1640, DMEM, Fetalbovine serum and Penicillin-Streptomycin were purchased from Gibco.Dimethyl sulfoxide (DMSO) was purchased from Sigma.

Inhibition Activity of Cell Proliferation

To investigate whether a compound is able to inhibit the activity ofEGFR and ErbB2 in cells, a mechanism-based assay using BT474 (EGFRoverexpression) and N87 (EGFR and ErbB2 overexpression) cell wasdeveloped. In this assay, inhibition of EGFR and ErbB2 was detected bythe inhibition of BT474 and N87 cells proliferation. BT474 cells werecultured in culture flasks to 40-80% confluence in DMEM plus 10% fetalbovine serum. N87 cells were cultured in culture flasks to 40-80%confluence in RPMI-1640 plus 10% fetal bovine serum. Cells werecollected and plated onto 96-well plates at desired cell density (BT474:1000 cells/well; N87: 1000 cells/well). BT474 plates were incubated 48 hat 37° C., with 5% CO₂ to adhere. N87 plates were incubated overnight at37° C., with 5% CO₂ to adhere. Compounds were added to the plates, Thefinal compound concentrations were 1000, 333.3, 111.1, 27.04, 12.35,4.12, 1.37, 0.46 and 0.15 nM. Place BT474 plates at 37° C., with 5% CO₂for 7d. Place N87 plates at 37° C., with 5% CO₂ for 72 h. After removingthe medium, 20 μl MTS/100 μl medium mixture solution were added to eachwell and incubate the plates for exactly 2 hours. Measure absorbance at490 nm and 650 nm (reference wavelength). IC₅₀ was calculated usingGraphPad Prism 5.0.

Select compounds prepared as described above were assayed according tothe biological procedures described herein. The results are given in thetable 1.

TABLE 1 BT474 N87 EXAMPLE NAME IC₅₀ (nM) IC₅₀ (nM) 1(E)-N-(4-(3-chloro-4-fluorophenylamino)-7- 2.3 5.0methoxyquinazolin-6-yl)-4-(2- (hydroxymethyl)azetidin-1-yl)but-2-enamide2 (R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7- 1.6 1.6methoxyquinazolin-6-yl)-4-(2- (methoxymethyl)azetidin-1-yl)but-2-enamide3 (S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7- 21.5 14.2methoxyquinazolin-6-yl)-4-(2- (methoxymethyl)azetidin-1-yl)but-2-enamide4 (R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7- 2.0 1.6ethoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin- 1-yl)but-2-enamide5 (S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7- 7.8 8.1ethoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin- 1-yl)but-2-enamide6 (R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2- 1.4 1.9methoxyethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide 7(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2- 5.8 4.6methoxyethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide 8(E)-N-(4-(3-chloro-4-fluorophenylamino)-7- 9.5 11.8(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide 9(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7- 6.6 15.5(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide 10(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7- 21.7 32.8(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide 11(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-((S)- 3.9 9.6tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide 12(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-((S)- 2.9 1.5tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide 13(E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro- 2.7 13.54-fluorophenylamino)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide 14(E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro- 2.9 1.24-fluorophenylamino)quinazolin-6-yl)-4-((R)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide 15(E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro- 25.0 11.24-fluorophenylamino)quinazolin-6-yl)-4-((S)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide 16(E)-N-(7-(((S)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro- 17.5 39.54-fluorophenylamino)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide 17(E)-N-(7-(((S)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro- 4.8 5.04-fluorophenylamino)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide 18(E)-N-(7-((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6- 10.8 11.2ylmethoxy)-4-(3-chloro-4- fluorophenylamino)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide 19(E)-N-(7-((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6- 2.9 2.8ylmethoxy)-4-(3-chloro-4- fluorophenylamino)quinazolin-6-yl)-4-((R)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide 20(E)-N-(7-((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6- 22.2 15.6ylmethoxy)-4-(3-chloro-4- fluorophenylamino)quinazolin-6-yl)-4-((S)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide

N87 Tumor In Vivo Study

Female BALB/cA-nude mice were implanted with NCI-N87 tumor cells. Tumormeasurements were recorded twice a week. Randomize animals to groups(Day 0) when tumors reached an average size of 60-150 mm³. Group sizewas 6 mice. Test compound was administered p.o. once daily for 21 days.Tumor inhibition values were determined at Day 21.

Tumor inhibition for provided compounds were shown in FIG. 1 and Table2. Tumor volume (V) was calculated as follow: V=½×a×b, where a and b arethe length and width of the tumor respectively. Relative tumorproliferation rate was calculated as follow: T/C (%)=(T−T₀)/(C−C₀)×100,where T and C are the tumor volume of test compound group and controlgroup on Day 21, T₀ and C₀ are the tumor volume of test compound groupand control group on Day 0.

TABLE 2 Tumor inhibition of test compounds Dosage Average Tumor Volume(mm³) T/C Inhibition Example (mg/kg) Day 0 Day 21 (%) rate (%) Vehicle —115.0 ± 3.6 1324.8 ± 122.5 — — Control 2 2 113.3 ± 4.4 584.4 ± 71.3 3961 2 5 117.6 ± 7.2 54.3 ± 3.8 −54 154 4 2 105.6 ± 9.9 436.6 ± 60.5 27 734 5  109.1 ± 10.1 49.7 ± 5.4 −54 154 6 5 116.9 ± 7.8 176.3 ± 24.2 5 95 610 114.8 ± 7.8 49.0 ± 3.9 −57 157 9 5 124.1 ± 8.5 349.3 ± 43.8 19 81 910  120.2 ± 13.0 60.3 ± 6.9 −50 150 Afatinib 20 117.2 ± 8.3 72.9 ± 7.9−38 138 Lapatinib 320 124.4 ± 7.3 277.3 ± 74.1 13 87

1. A compound of formula (I):

and/or a pharmaceutically acceptable salt thereof, wherein: R¹ and R²are independently selected from hydrogen and C₁₋₆ alkyl, wherein Alkylis substituted with at least one substituent independently selected fromthe group consisting of hydroxyl and C₁₋₆alkoxy; R³ is selected fromC₁₋₆ alkoxy, C₃₋₆ cycloalkoxy, tetrahydrofuran-3-yloxy,tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy,tetrahydropyran-4-yloxy, tetrahydropyran-4-ylmethoxy,(1,4-dioxan-2-yl)methoxy, and (3-oxa-bicyclo[3.1.0]hexan-6-yl)methoxy,wherein alkoxy and cycloalkoxy are independently unsubstituted orsubstituted with at least one substituent, such as one, two, three, orfour substituents, independently selected from the group consisting ofhalogen, hydroxyl, C₁₋₆ alkyl, C₃₋₆ cycloAlkyl and C₁₋₆ alkoxy; and Aris selected from aryl, wherein aryl is substituted with at least onesubstituent, such as one, two, three, or four substituents,independently selected from the group consisting of halogen, hydroxyland cyano.
 2. A compound of claim 1 and/or a pharmaceutically acceptablesalt thereof, wherein R² is hydrogen.
 3. A compound of claim 1, and/or apharmaceutically acceptable salt thereof, wherein R¹ is C₁₋₆ alkyl,wherein alkyl is substituted with at least one substituent independentlyselected from the group consisting of hydroxyl and C₁₋₆ alkoxy.
 4. Acompound of claim 3, and/or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from hydroxymethyl, methoxymethyl andethoxymethyl.
 5. A compound of claim 1, and/or a pharmaceuticallyacceptable salt thereof, wherein R³ is selected from methoxy, ethoxy,methoxyethoxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy,tetrahydrofuran-2-ylmethoxy, tetrahydrofuran-3-ylmethoxy,tetrahydropyran-4-yloxy, tetrahydropyran-4-ylmethoxy,(1,4-dioxan-2-yl)methoxy, and (3-oxa-bicyclo[3.1.0]hexan-6-yl)methoxy.6. A compound of claim 1, and/or a pharmaceutically acceptable saltthereof, wherein Ar is aryl, wherein aryl is substituted with at leastone substituent, such as one, two, three, or four substituents,independently selected from the group consisting of fluorine, chlorine,bromine and iodine.
 7. A compound of claim 6, and/or a pharmaceuticallyacceptable salt thereof, wherein Ar is 3-chloro-4-fluorophenyl.
 8. Acompound of claim 1, wherein the compound is selected from:(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-methoxyethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;(R,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(S,E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(cyclopropylmethoxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-((S)-tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(4-(3-chloro-4-fluorophenylamino)-7-((S)-tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-((R)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(7-(((R)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-((S)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(7-(((S)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(7-(((S)-1,4-dioxan-2-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-(2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(7-((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-(2-(hydroxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(7-((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-((R)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide;(E)-N-(7-((1R,5S,6R)-3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)-4-((S)-2-(methoxymethyl)azetidin-1-yl)but-2-enamide;and/or pharmaceutically acceptable salts thereof.
 9. A pharmaceuticalcomposition, comprising a compound of claim 1, and/or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.
 10. A method to treat, ameliorate or prevent a condition, whichresponds to inhibition of ErbB family of receptor kinase, comprisingadministering to a subject in need of such treatment an effective amountof a compound of claim 1, and/or a pharmaceutically acceptable saltthereof, and optionally in combination with a second therapeutic agent.11. (canceled)
 12. A method to treat, ameliorate or prevent a condition,which responds to inhibition of ErbB family of receptor kinase,comprising administering to a subject in need of such treatment aneffective amount of a pharmaceutical composition of claim 9, andoptionally in combination with a second therapeutic agent.